This is a request for a Liquid Chromatography - tandem Mass Spectrometry (LC- MS/MS) instrument that will be utilized by a major user group of five investigators at The Scripps Research Institute (TSRI) and also by a minor user group of investigators from TSRI and neighboring institutions. The requested LC-MS/MS will be used for the analysis of neuroactive peptides, endogenous cannabinoids and exogenous drugs and their metabolites in brain tissue, in vivo brain microdialysates and plasma. These analyses will directly advance research that is currently funded by NIH awards. Several characteristics of the LC-MS/MS will facilitate the research of the major and minor user groups. First, mass spectrometers provide a form of "universal detection" that offers much greater molecular specificity than is typically provided through electrochemical, spectrophotometric or immunoassay detection methods. Second, tandem mass spectrometers (MS/MS) provide substantially higher signal-to-noise ratios and considerably greater analyte specificity than do single quadrupole mass spectrometers, providing substantially lower limits of quantitation in complex biological matrices. Third, the requested capillary liquid chromatography (LC) system substantially enhances mass sensitivity and is very well suited for the separation of small volume (<10 ?l) samples containing extremely low analyte concentrations (pM - nM) while providing flexibility for analysis of larger sample volumes as needed. The LC-MS/MS will be housed in a shared facility at TSRI that is equipped for the immediate installation of the instrument without need of renovation. TSRI has made a financial commitment to the long-term maintenance and operation of the instrument inclusive of service contracts, supplies and support of the technical staff. A highly qualified technical staff will provide user training and instrument maintenance and an Internal Advisory Committee will assure equitable instrument use by investigators both within and outside the major user group. The LC- MS/MS instrument will have a major impact on the successful completion and renewal of 22 NIH-funded research projects within the major user group that include individual R01 research projects, two NIH-funded Research Centers and one NIH-funded Program Project. Importantly, the results gathered with the requested instrument are likely to provide novel insight into the neural mechanisms contributing to drug and alcohol abuse, eating disorders, chronic pain, and psychiatric disorders such as anxiety and depression. HEALTH RELEVANCE: The requested LC-MS/MS instrument will provide the ability to quantify very low levels of neuroactive substances in biological samples including brain microdialysates. This will directly impact the progress and success of more than 22 NIH-funded research projects. The results gathered with the requested instrument will provide novel insight into the neural mechanisms contributing to drug and alcohol abuse, eating disorders, chronic pain and psychiatric disorders such as anxiety and depression.